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Upregulation of dynorphin/kappa opioid receptor system in the dorsal hippocampus contributes to morphine withdrawal-induced place aversion

Abstract

Aversive emotion of opioid withdrawal generates motivational state leading to compulsive drug seeking and taking. Kappa opioid receptor (KOR) and its endogenous ligand dynorphin have been shown to participate in the regulation of aversive emotion. In the present study, we investigated the role of dynorphin/KOR system in the aversive emotion following opioid withdrawal in acute morphine-dependent mice. We found that blockade of KORs before pairing by intracerebroventricular injection of KOR antagonist norBNI (20, 40 μg) attenuated the development of morphine withdrawal-induced conditioned place aversion (CPA) behavior. We further found that morphine withdrawal increased dynorphin A expression in the dorsal hippocampus, but not in the amygdala, prefrontal cortex, nucleus accumbens, and thalamus. Microinjection of norBNI (20 μg) into the dorsal hippocampus significantly decreased morphine withdrawal-induced CPA behavior. We further found that p38 MAPK was significantly activated in the dorsal hippocampus after morphine withdrawal, and the activation of p38 MAPK was blocked by pretreatment with norBNI. Accordingly, microinjection of p38 MAPK inhibitor SB203580 (5 μg) into the dorsal hippocampus significantly decreased morphine withdrawal-produced CPA behavior. This study demonstrates that upregulation of dynorphin/KOR system in the dorsal hippocampus plays a critical role in the formation of aversive emotion associated with morphine withdrawal, suggesting that KOR antagonists may have therapeutic value for the treatment of opioid withdrawal-induced mood-related disorders.

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Fig. 1: Conditioned place aversion was induced by naloxone-precipitated morphine withdrawal in mice.
Fig. 2: Effects of norBNI by intracerebroventricular (icv) administration on conditioned morphine withdrawal-induced CPA behavior.
Fig. 3: The expression levels of dynorphin A in different brain regions after morphine withdrawal.
Fig. 4: Effects of norBNI by intra-dorsal hippocampal administration on morphine withdrawal-induced CPA behavior.
Fig. 5: KOR dependent p38 MAPK activation was involved in the CPA produced by morphine withdrawal.
Fig. 6: Effects of norBNI and SB203580 in the dorsal hippocampus on the novel object recognition test task.

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Acknowledgements

This research was supported by grants from the Ministry of Science and Technology (2021ZD0203500 to YJW; 2021ZD0202900 to JGL), from the National Natural Science Foundation of China (82030112 to JGL, 81773710 to YJW), from Science and Technology Commission of Shanghai Municipality (20ZR1468200 to YJW) and from Shenzhen-Hong Kong Institute of Brain Science—Shenzhen Fundamental Research Institutions (NYKFKT2019015 to JGL).

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YJW, CXY, and JGL designed the experiments. YC and CYW performed the experiments with the assistance of GYZ, SYY, YZD, XLS, WWW, and YM, YC, CYW, and YJW performed data statistical analysis. YC, GYZ, and YJW wrote the manuscript, and YJW, CXY, and JGL revised it.

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Correspondence to Yu-jun Wang or Chang-xi Yu.

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Chen, Y., Wang, Cy., Zan, Gy. et al. Upregulation of dynorphin/kappa opioid receptor system in the dorsal hippocampus contributes to morphine withdrawal-induced place aversion. Acta Pharmacol Sin (2022). https://doi.org/10.1038/s41401-022-00987-3

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  • DOI: https://doi.org/10.1038/s41401-022-00987-3

Keywords

  • morphine withdrawal
  • conditioned place aversion
  • kappa opioid receptor
  • p38 MAPK
  • norBNI
  • dorsal hippocampus

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